Association Between Hemostatic Profile and Migraine: A Mendelian Randomization Analysis

Yanjun Guo; Pamela M Rist; Maria Sabater-Lleal; Paul de Vries; Nicholas Smith; Paul M Ridker; Tobias Kurth; Daniel I Chasman

doi:10.1212/WNL.0000000000011931

Association Between Hemostatic Profile and Migraine: A Mendelian Randomization Analysis

Neurology. 2021 May 18;96(20):e2481-e2487. doi: 10.1212/WNL.0000000000011931. Epub 2021 Apr 1.

Authors

Yanjun Guo¹, Pamela M Rist¹, Maria Sabater-Lleal¹, Paul de Vries¹, Nicholas Smith¹, Paul M Ridker¹, Tobias Kurth¹, Daniel I Chasman²

Affiliations

¹ From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.
² From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany. dchasman@research.bwh.harvard.edu.

Abstract

Objective: To assess support for a causal relationship between hemostatic measures and migraine susceptibility using genetic instrumental analysis.

Methods: Two-sample Mendelian randomization instrumental analyses leveraging available genome-wide association study (GWAS) summary statistics were applied to hemostatic measures as potentially causal for migraine and its subtypes, migraine with aura (MA) and migraine without aura (MO). Twelve blood-based measures of hemostasis were examined, including plasma level or activity of 8 hemostatic factors and 2 fibrinopeptides together with 2 hemostasis clinical tests.

Results: There were significant instrumental effects between increased coagulation factor VIII activity (FVIII; odds ratio [95% confidence interval] 1.05 [1.03, 1.08]/SD, p = 6.08 × 10^-05), von Willebrand factor level (vWF; 1.05 [1.03, 1.08]/SD, p = 2.25 × 10^-06), and phosphorylated fibrinopeptide A level (1.13 [1.07, 1.19]/SD, p = 5.44 × 10^-06) with migraine susceptibility. When extended to migraine subtypes, FVIII, vWF, and phosphorylated fibrinopeptide A showed slightly stronger effects with MA than overall migraine. Fibrinogen level was inversely linked with MA (0.76 [0.64, 0.91]/SD, p = 2.32 × 10^-03) but not overall migraine. None of the hemostatic factors was linked with MO. In sensitivity analysis, effects for fibrinogen and phosphorylated fibrinopeptide A were robust, whereas independent effects of FVIII and vWF could not be distinguished, and FVIII associations were potentially affected by pleiotropy at the ABO locus. Causal effects from migraine to the hemostatic measures were not supported in reverse Mendelian randomization. However, MA was not included due to lack of instruments.

Conclusions: The findings support potential causality of increased FVIII, vWF, and phosphorylated fibrinopeptide A and decreased fibrinogen in migraine susceptibility, especially for MA, potentially revealing etiologic relationships between hemostasis and migraine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
Factor VII / metabolism
Factor VIII / metabolism
Factor XI / metabolism
Fibrin Fibrinogen Degradation Products / metabolism
Fibrinogen / metabolism
Fibrinopeptide A / metabolism
Genetic Predisposition to Disease
Genome-Wide Association Study
Hemostasis / genetics*
Humans
International Normalized Ratio
Mendelian Randomization Analysis
Migraine Disorders / blood
Migraine Disorders / epidemiology
Migraine Disorders / genetics
Migraine with Aura / blood
Migraine with Aura / epidemiology
Migraine with Aura / genetics*
Migraine without Aura / blood
Migraine without Aura / epidemiology
Migraine without Aura / genetics*
Partial Thromboplastin Time
Plasminogen Activator Inhibitor 1 / blood
Prothrombin Time
Tissue Plasminogen Activator / blood
von Willebrand Factor / metabolism

Substances

Fibrin Fibrinogen Degradation Products
Plasminogen Activator Inhibitor 1
fibrin fragment D
fibrinopeptide A, phospho-Ser(3)-
von Willebrand Factor
Fibrinopeptide A
Factor VII
Factor VIII
Fibrinogen
Factor XI
Tissue Plasminogen Activator

Abstract

Publication types

MeSH terms

Substances

Grants and funding